2-lower-alkyl pregnenes and process therefor



United States Patent m Z-LOWER-ALKYLPREGNENES AND PROCESS THEREFOR Frank H. Lincoln, Jr., and John A. Hogg, Kalamazoo Township, Kalamazoo County, Mich'., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No'Dra'wing, 'pplicatio'n January '31, 1955 Serial No; 485,318

20' Claims. (ct. zen-391.1

This invention relates to novel steroids, more particularly to synthetic steroid hormones, to novel steroid intermediates in theproduction of these synthetic steroid hormones and jto the process for their production.

The novel compounds of the present invention and the process for their production may be represented by the following formulae:

CHr-O-R CHa-O-R CHrO-R III CHa-O-AO wherein R is hydrogen or the 'acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, R is hydrogen, lower-alkoxy, trifiuoromethyl or carbo-lower-alkoxy, R" is lower-alkyl and Ac is the acyl radical of a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclu- 5 srve.

It is an object of the vpresent invention to provide synthetic steroid hormones. Another object is the provision of steroid intermediates readily convertible to these synthetic steroid hormones. Still another object is the .pro- 7 vision ofa process for the production of these synthetic gteroid hormones. A- fur'therobject is "the provision of "ice a process for the introduction of an alkyl group into the cyclopentanopolyhydrophenanthrene nucleus of 115,21 dihydroxy-4,l7(20) pregnadiene 3 one and 21 esters thereof. Other objects will be apparent to those skilled in the art to which this inventionpertains. I According to the present invention, l1B,21-dih'ydroxy- 4,17(20) pregnadiene-3-one, or a 2l-ester thereof (I) converted to the novel hormone-like steroids of the pres-' ent invention by the following reactions: first, glyoxala tion, carboxylation, trifiuoroacetylation or formylation to produce a 2-carbonyl derivative (11); second, alkylation to produce the corresponding 2'-lower-alkyl-2-carbonyl compound (III); third, removal of the Z-carbonyl group to produce the 2-lower-alky1 compound (IV); fourth, esterification of the thus-produced 21-hydroxy compound to produce a 2l-esterified compound (V); and fifth, oxida tive hydroxylation of the A double bond to produce a synthetic steroid hormone (VI).

Hydrolysis of the 2l-ester group, e.g., with aqueous sodium bicarbonate in methanol, is productive of the corresponding 21-hy-' droXy compound. Each of these reactions will be discussed in detail hereinafter.

The starting 1 118,2 l-dihydroxy-4, 1 7 (20) -pregnadiene-3- one is prepared by reacting ll-ketoprogesterone with about a molar equivalent of sodium methoxide and about 2.75 molar equivalents of diethyl oxalate in benzene, brominating the thus produced sodium euolate with about two molar equivalents of bromine and reacting the bro minated product with sodium'methoxide and methanol 'to produce methyl 3,11 diketo 4,17(20) pregnadiene-21- oate. Ketalizing the 3-keto group with ethylene glycol followed by reduction with lithium aluminum hydride and subsequent hydrolysis of the thylene glycol ketal group with aqueous acid isproductive of 1118,21-dihydroxy-4,l7(20)-pregnadiene-3-one. The production of 11 fl,21-dihydroxy-4,17(20) pregnadiene 3 one and 21'- esters thereof is disclosed in U.S. Patent 2,774,776. The ill-esters of 11,8,21 dihydroxy 4,17(20)-pregnadiene 3- one are prepared by the reaction of the latter compound with the selected esterification agent, e.g., an acid chloride or anhydride in pyridine, an acid in the presence of an esterification catalyst, or an ester under ester exchange reaction'conditions. Examples of 11fi-hydr oxy-21- acylwry-4,17(20)-pregnadiene-3-ones thus-prepared are described in the examples hereinafter. I

Starting with 21 acetoxy 4,l7(20)-pregnadiene-3,l ldione, the ll-keto analogue of (I), or other 2l-esters thereof, which can be prepared by the oxidation of the corresponding 2l-ester of 1lfi,21.- dihydroxy 4,17(20)- pregnadiene-3-one (I) at the ll-position, and proceeding with the reactions described above, there is thus-produced the corresponding 2l-ester of a 2-lower-a1kyl-l'7a,21- dihydroiry-4-pregnene-3,1l,20-trione. These steroids also possess remarkable cortical hormone activity markedly different from the corresponding esters of l7a,21-dihydroxy-4-pregnene-3,11,20-trione. Especially outstanding among these compounds are Z-methyl-l7a,2 l-dihydroxy 4-pregnene-3,1 1,20-trione and the 21-esters thereof wherein the ester group is lower-acyloxy and preferably aceto'xy.

The novel 2-lower-alkyl-1 1 3,17u-dihydroxy-2l-acyloxy- 4-pregnene-3,20-diones of the present invention are converted to other novel hormonal syntheticsteroids by the following reactions, exemplified by the use of Z-methyl- 11B,17oz dihydroxy-Z1-acetoxy-4-pregnene 3,20 --dione: Dehydration of 2-methyl11B,17a-dihydr0Xy-2l-acetoxy 4-pregnene-3,20-dione, for example, byreaction with a dehydrating agent, e.g., paratoluenesulfonic acid, POCl in pyridine, HCl in acetic acid, acetic or formic acid in .the presence of BF is productive of 2-methyl-l7 ehydroxy-21-aceto y-4,9 1 1 pregnadiene-3 ,20 dione compound, for example, with a methylene chloride solution of a molar equivalent of hydrogen fluoride at minus fifteen degrees centigrade, is productive of 2-methyl-9afluoro-l1B,l7a-dihydroxy-2l-acetoxy 4 pregnene 3,20- dione. Substitution of hydrogen chloride for the hydrogen fluoride at about zero degrees centigrade is productive of 2-methyl-9a-chloro-11B,l7a-dihydroxy-2l-acetoxy- 4-pregnene-3.20-dione. These latter two compounds, and especially the 9oc-fill0l0 compound, possesses remarkable hormonal properties. Their activity spectrum, e.g., mineralocorticoid, glucocorticoid and anti-inflammatory activity is of a different order and kind from any of the natural or known synthetic adrenal cortical hormones. Their anti-inflammatory activity is of an especially high order of activity.

Substitution of another 2 lower alkyl-l1B,l7a-dihydroxy-Zl-acyloxy-4-pregnene-3,20-dione as the starting steroid in the reactions described above is productive of the corresponding 2-lower-alkyl-9u-chloro or fluorol 119, l7a-dihydroxy-2l -acyloxy-4-pregnene-3 ,20-dione.

The novel 2 lower alkyl 1lfi.l7cz,2l trihydroxyipregnene-3,20-dione and 21-esters thereof have a high order of physiological activity, and possess an entirely different ac ivitv s e trum than the adrenal cor ical hormone hydrocortisone. The novel cortical synthetic steroid hormones of the present invention possess antiinfiam nat rv. u oc tico d. and mineralnc rticoid activity of a high order. Their surprising pattern of physiological activity is exemplified by the discovery that Z-methyl-l 1n,l7a-dihydroxy-2l-acetoxy-4-pregnene- 3,20-dione has both mineralocorticoid and anti-inflammatory activity of a very high order whereas desoxy- V corticosterone and its acetate has little or no anti-inflammatory activity, but has pronounced mineralocorticoid activity and hydrocortisone and its acetate has marked anti-inflammatory activity but a very low order of mineralocorticoid activity. For example, the 2-methyl synthetic cortical hormone of the present invention has an anti-inflammatory activity about seven times as great as hydrocortisone by the cotton wad test and a mineralocorticoid activity significantly greater than hydrocortsone acetate. The 2-methyl compound of the present invention is about four times as active orally as hydrocortisone acetate in causing adrenal, splenic and thymic involution in test animals but contrary to desoxy- 2-lower-alkyl homologues of the present invention and 2l-ester's thereof, respectively, are substitutable therein.

corticosterone acetate, caused no renal hypertrophy. The

compound of the present invention is about seven times as active as hydrocortisone in the work test for glucocorticoid activity and has marked glucocorticoid activity by the glycogen deposition assay.

The novel compounds of the present invention (VI), especially the 2-methyl compounds are useful in the treatment of maladies in both humans and valuable domestic animals. e.g., inflammations of the skin and eyes, caused by bacterial or fungal infections, contact dermititis or physiological maladjustment.

The novel 2 lower alkyl-l1 8,l7u,21-trihydroxy-4- pregnene 3,20 dione and 2-loWer-alkyl-11,3,17a-dihydroxy-2l-acyloxy-4-pregnene-3,20-diones of the present invention are especially useful as pharmaceutical compositions and mixtures, e.g., ointments, lotions, greases, creams, aqueous suspensions, etc., for topical use. Examples of especially advantageous pharmaceutical compositions are listed below. Although the examples are to the 2-methyl-1lfl,17u,2l-trihydroxy-4-pregnene-3,20- dione and 2 methyl 1lfi,17u-dihydroxy-21-acetoxy-4- pregnene-3,20-dione, it is to be understood that the other The novel 2-methyl-l l 6, l7a-dihydroxy-2 l -acetoxy-4- pregnene-3,20-dione is advantageously employed as a topical ointment for useon the skin or in the eyes in the treatment of topical'inflammatory conditions. A suitable topical and ophthalmic. ointment has the following composition:

' J Lbs.

20 percent Wool fat, U.S.P; 100

25 percent white mineral oil, U.S.-P 125 0.5 percent 2 methyl 115,17a-dihydroxy-2l-acetoxy- 4-pregnene-3,20-dione (micronized). 2.5

White petrolatum, U.S.P., q.s.i ad 500 lbs.

The wool fat and petrolatum are melted and strained into a suitable container. The temperature is adjusted to 113 degrees Fahrenheit. Thesteroid is mixed with ninety pounds of strained mineral oil and milled through a Fitzpatrick mill. The mill is washed with 35 pounds of strainedv mineral oil. I The steroidmixture and mill washings are added to the base and the base'then stirred with a high speed mixer until congealed.

Incorporation of an antibiotic in the ointment, especially neomycin sulfate, has surprising therapeutic advantages each active ingredient potentiating and supplementing the useful properties of the other in a fashion more particularly described in the copending applica tion of Dale, Ser. No. 458,679, filed September 27, 1954. Such an ointment is as follows:

20 percent wool fat', U.S.P 100 25 percent white mineral oil, U.S.P 125 0.6 percent neomycin sulfate (microatomized) 3 1.0 percent Z-methyl-l15,17a-dihydroxy-2l-acetoxy- 4-pregnene-3,20-dione (micronized) 5 White petrolatum, U.S.P., q.s. ad 500 lbs.

An injectable composition suited for suspending the compounds of the present invention, which has advantages in the treatment of Addisonian crisis and in shock is as follows:

Mg. Sodium citrate, U.S.P 5.7 Sodium carboxymethylcellulose, low viscosity... 2.0 Plasdone (polyvinylpyrrolidone) 10.0 Polysorbate 80, U.S.P 4.0 Sterile methylparaben, U.S.P 1.5 Sterile propylparaben, U.S.P 0.2 Z-methyl-l 113,17a-dihydroxy-2l-acetoxy-4-pregnene- 3,20-dione 10.0

Water for injection, sufficient to make up 1.0 cc.

2.5 grams sterile micronized 2-methyl-11B,17a,21-trihydroxy-4-pregnene-3,20-dione 3.0 grams Polyethylene Glycol 4000 0.9 gram sodium chloride gran., U.S.P.

0.4 gram Tween 1.5 grams benzyl alcohol, Q.s. cc. water. for injection The polyethylene glycol, sodium chloride, Tween80 and benzyl alcohol are dissolved in'water and the soluaaasrtam trihydroxy-4-pregnene 3,20-dione or 2'l-ester thereofby' reactions described in. detail hereinafter.

CONDENSATION In carrying out the condensation, l1,9,2l-dil'i'ydroxy- 4,l7(20) pregnadiene-3-one or 2l-est er thereof is admixed with the selected alkali-metal condensation catalyst and dialkyl ester of oxalic acid, orcarboni'c acid'or alkyl ester of trilluor'oacetic or formic acid in an 'organic'solvent therefor, the order of mixing being non-critical, to produce the alkali-metal salt of a compound represented by Formula II wherein R is hydrogen or the acyl radical of a carboxylic acid and R is hydrogen, lower-alkoxy, t'rifiuoromethyl or carbo-lower-alkoxy, i.e., the 2-carbonyl group is formyl, COO-lower-alkyl, CF3CO-' or COCOOlower-alkyl, respectively.v The free enol is conveniently prepared by the neutralization of an aqueous solution of an alkali-metal enolate thereof, thus precipitating'the free enol. Preferred startin steroids are those represented by Formula I wherein R is the acyl radical of a hydrocarbon carboxylic' acid containing fromone to twelve carbon atoms, inclusive, especially aliphatic acids containing from. one to eight carbon atoms, inclusive, preferably acetic.

Reaction solvents which can conveniently beemployed in the condensation include benzene, toluene, xylene, and like aromatic hydrocarbons, methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol, and other alcohols, tetrahydrofuran, dioxane, diethyl ether, Skellysolve B hexane hydrocarbons and other aliphatic hydrocarbons, mixtures of these solvents, and other essentially non-reactive solvents. BenZene With or: without small percentages of,

added alkanol, or tertiary butyl j alcohol are usually the:-

preferred solvents.

The condensation, is. usually conducted ture between about zero degrees centigrade and theboiling point of the reaction mixture. Usually the reaction proceeds with satisfactory rapidity atbetween about room temperature and about seventy degrees centigrade, and temperatures substantially above or below this range are therefore, usually not employed. However, when other than the methyl or ethyl ester of formic, carbonic or oxalic acid or when bases weaker than sodiumv methoxide or ethoxide are employed, temperatures substantially higher than, the preferred range may be required to obtain a satisfactory yield of carbonyl substituted product.

The time necessary to obtain substantially complete reaction varies considerably between about five minutes and, several days, depending upon the reaction solvent, the reaction temperature, the selected ester of formic,

carbonic, CF COOH or oxalic acid, and the alkali-metal.

condensation catalyst employed, the moisture present in the reaction, and the molar ratios of the reactants. When sodium methoxide, methyl or ethyl formate, carbonate or oxalate and tertiary butyl alcohol are employed at about fifty degrees Centigrade, the reaction is usually more than half completed in a few minutes.

The condensation step is usually carried out in the absence of any significant amounts of water in any form in the reaction, as would be expected in a reaction of this type. To ensure the essentially complete exclusion of water from the reaction mixture, the solvent is usually carefully dried with a drying agent such as, for example, anhydrous sodium sulfate, calcium sulfate, calcium chlo ride, phosphorous pentoxide, sodium, or the like, or when an aromatic hydrocarbon is used as the solvent, a portion of the solvent is distilled before using.

Since the reaction is somewhat reversible, i.e., there-' action product in the presence of a large amount of an at a tempera-- amount; of base may undergo alcoholysis to give starting,

material, the. Presence of a large amountof methanol: or ethanol in the-reaction mixture is usually-not desirable although satisfactory amounts. of product have beenobtained using ethanol as the sole reaction solvent.

Alkali-metal condensation catalysts'includes the alkalimetal alkoxides, e.g., sodium methoxide, sodiumethoxide,

sodium isopropoxide, potassium tertiary butoxide, lithium methoxide, and the like, thealkali metals, the alkalimetal hydrides, alkali metal amidesv and alkyl alkali" metals, e.g. sodium amide, triphenyl methyl sodium, .andthe like. Of these,-the alkali-metal alkoxides, especially sodiummethoxide and sodium ethoxide, are preferredfor their convenience. and consistently satisfactory results. The alkali-metal alkoxide may be used solvent-free, dissolved or suspended in a non-reactive solvent, or in situ in the alkanol in which said alkali-metal alkoxide was" prepared. When potassium is used, it is usually used; as

the. solution, formed by its reaction with. tertiary butyl alcohol according to procedure well known inthe art.

The theoretical alkali-metal condensation. catalyst required is one. mole per mole of steroid. Somewhatmore',

advantageous and promotes rapid completion of,there-' action. The reaction is therefore usually carried out inthe presence ofgreater than about one molar equivalent of-the' selected ester. Esters, preferably of oxalioacid, which are conveniently employed in. theprocess of the presentv invention include. the lower-alkyl esters, e.g.,

methyl, ethyl, and the propyl, butyl, isobutyl, amyl, hexyl, heptyl, and octyl esters of formic, carbonic oroxalic acid, and thelike. Since the methyl and ethyl. esters appear to. undergo condensation with the starting steroid themost rapidly, these esters are usually employed with methyl oxalate and ethyl oxalate being especially preferred.

The thus produced alkali-metal enolate may be separated by the addition of a large volume ofan organic solvent in which the-alkali-metal enolate is insoluble, such as ether, pentane, or benzene, for example. Another method of producing a somewhat purer alkali-metalenolatecomprises acidification of a cold aqueous solution of the thusprecipitated alkali-metal enolate to precipitate the free enol and then treating a solution of the free enol in ether or benzene with a chemical equivalent of sodium" methoxide, thus reprecipitating'the sodium enolate. When" the "condensation is carried out in the presence of substantial amounts of methyl or ethyl alcohol, theremovalof' said alcohol by distillation at reduced pressure before the addition of an additional amount of solvent is preferred; if a high yield of isolated product is to be obtained.

ALKYLATION.

Thealkylation involves the alkylation of the alkalimetal salt of a 2-carbonyl-1IB-hydroxy-Zl-oxy-4,l7(20)-' pregnadiene-3-one represented by' Formula. II with. a

bonyl-Z-lower-alkyll 1 ,B-hydroxy-Z l-oxy-4, 17 (20 )i-pregnadiene represented by Formula III.

The alkali-metal salt of a compound represented. by" Formula 11- may be in the form of the pure' isolated" alkali-metal salt of the product of the condensation re action (II), e.g.,. potassium, lithium or sodium salt, or

in the form of a solution of the free active-methylenev compound (II) mixed with an alkali-metal alkylation catalyst,-e'.g., the alkali-metal alkoxides, preferably com taining: from one to'eight carbon atoms,.inclusive, e.g,.',. sodiummethoxide,; sodium ethoxide, lithium methoxide, potassium ternarybutoxide, etc.,.. the alkali-metals, the

alkali-metal hydrides, the alkali-metal amides, triphenyl-- methyl sodium, the alkali-metal carbonates; e.g., sodium or potassium carbonate, etc., i.e., a base capable of forming a salt with an active methylene compound, in solution or suspension. The presence of a molar excess of alkylation catalyst appears to be sometimes advantageous if the catalyst is relatively weak, e.g., an alkali-metal carbonate.

The usual reaction conditions and solvents employed in.

the alkylation of an active methylene compound are employed in the alkylation process. The reaction is usually continued for several hours, e.g., about eight to about 72, at a reaction temperature of about room tem-.

perature although higher reaction temperatures shorten this reaction time considerably. I A convenient method of alkylation involves the addition of the selected alkyl halide to the reaction product 1 resulting from the condensation step, preferably after the decomposition of any excess alkali-metal condensa tion catalyst. Satisfactory yields are also obtained by stirring a solution of the free active methylene compound ('II) with the selected alkyl halide in the presence of the selected alkali-metal alkylation catalyst.

The alkylation product is a 2-lower-alkyl-2-carbonyl- 115 hydroxy 2l-oxy-4,l7(20)-pregnadiene-3-one (III) REVERSAL The reversal step of the present invention involves the removal of the carbonyl, i.e., formyl, carboalkoxy, trifluoroacetyl or alkoxyoxalyl, group from the 2-position leaving the alkyl group, at the 2-position thus producing a 2 lower-alkyl-l lp-hydroxy-2l-oxy-4,17(20)-pregnadi-.

ene-3-one represented by Formula IV. The reversal of an acetoacetic ester condensation in disubstituted acetoaceticester is a recognized phenomenon. See Organic Reactions, Wiley publishers, vol. I, 269 (1942), where alcoholic sodium ethoxide was found to produce the reversal phenomenon. n

The reversal step of the present invention is produced by thealkali-metal alkylation catalysts, in the presence of water or a lower-alkanol, i.e., the reversal is promoted by the presence of hydroxide or alkoxide ions, particularly methoxide and ethoxide ions. Thus there is produced a 2 -lower-alkyll 1 B-hydroxy-Z 1-oxy-4, 17 (20) -pregnadiene- 3-one of the present invention (IV).

Ordinarily, the 2l-oxy group of the compound produced in the reversal is a hydroxy group (IV, R=H) since the conditions which promote the reversal of the Z-carbonyl group also promote the alcoholysis of any 2-acyloxy group to produce a 21-hydrox'y. If the starting steroid for the condensation and/or alkylation step is a 2l-hydroxy group, then the reaction product of the reversal step will also be a 21-hydroxy group. The more hindered 2l-acyloxy groups, e.g., trimethylacetoxy, 2,6-disubstitutedbenzoxy, etc., will remain substantially intact during the reversal reaction whereas the unhindered groups, e.g., formoyloxy, acetoxy, and other a-unsubstituted hydrocarbon acids, etc., are almost completely converted to hydroxy groups. The degree of alcoholysis or hydrolysis of the partially'hindered 21-acyloxy groups will depend, in part, upon the reaction temperature and time and reactants promoting the reversal.

Soc.,

metal oxides or derivatives thereof include manganese,

The reaction product resulting from the reversal reaction will contain at least some 2-lower-alkyl-l1p,21-dihydroxy-4,17(20)-pregnadiene-3-one and frequently free 21-hydroxy steroid will be the sole reaction product, particularly if the starting steroid (I and/or II) is a 21-- hydroxy compound.

It is preferred in the oxidative hydroxylation of the reaction product of the reversal reaction that all the startingfsteroid for the oxidative hydroxylation be 21-acyloxy steroid (V). The reaction product (IV) is therefore reacted with an esterification agent.

The esterification step of the process of the present invention involves the conversion of the ZI-hydroxy group of a 2-lower-alkyl-llp,2l-dihydroxy-4,l7(20)-1 pregnadiene-S-one (IV) to a 2l-ester group ,(V). This.

can be performed under the esterification conditions known in the art, e.g., by the reaction of IV with the selected acid anhydride or acid chloride, preferably in" the presenceof pyridine, alkylpyridine or other N-cyclo aromatic tertiary amine; with the free acid, e.g., formic acid or a weaker acid in the presence of an esterification catalyst, e.g., para-toluenesulfonic acid or sulfuric acid; with an ester by ester interchange reaction; or by.

reaction with the ketene of the selected acid.

Since the llfi-hydroxy group is relatively labile, reaction conditions which are not apt to cause dehydration, or alteration in some other manner, of the llfl-hydroxy group are preferred. The preferred esterification reagent is an acetylating agent, e.g., acetic anhydride, preferably in the presence of pyridine, producing a compound represented by Formula V wherein Ac is acetyl.

OXIDATIVE HYDROXYLATION The oxidative hydroxylation step of the present invention consists of the reaction of a 2-lower-alltyl-l15-hydroxy-21 acyloxy-4,l7(20)-pregnadiene-3-one (V) with a hydroxylating agent and an oxidizing agent to produce a 2 lower alkyl-l15,17a-dihydroxy-21-acy1oxy-4-pregnene-3,20-dione (VI).

The hydroxylation of a A -2l-acyloxy steroid to' of the metal oxides, preferably from sub-groups IV, V

and VI of the periodic table, see Milas, I. Am. Chem. Soc., 59, 2342 (1937), and Mugden and Young, J. Chem. 1944, 2988. Examples of other hydroxylating dioxide, vanadium pentoxide, chromium trioxide, pertungstic acid, permolybdic acid, selenium dioxide, etc.

The first recognized example of an oxidative hydroxylation of a steroid is found in Prins and Reichstein, Helv. Chim. Acta, 25, 300 (1942). There is reported, using osmium tetroxide and chloric acid, the oxidative hydroxylation of a 13 steroid to produce a 20-keto-2lhydroxy steroid. The concept of oxidative hydroxylation outside the field of steroidal chemistry was first demonstrated, employing a catalytic amount of osmium tetroxide with hydrogen peroxide, by Criegee, Annalen.

9" The use of osmium tetroxide. and hydrogen peroxide in the oxidative hydroxylation. of certain A -2 1-sub stituted steroids is claimed in US. Patents 2,662,854 and 2,668,816. The use of amine oxide peroxides with osmium tetroxide in the oxidative hydroxylation ofA 21-acyloxy steroids is claimed in US. Patent 2,769,824 and the use of aryliodo oxides with osmium tetroxide in the oxidative hydroxylation of these same steroids is claimed in U.S. Patent 2,875,217. The use of hydrogen peroxide, an amine oxide peroxide or an aryliodo oxide as: the oxidizing agent in the oxidative hydroxylation of the present invention is preferred. The use of' these reagents is discussed more'fully below.

The amide oxide peroxides which may be employed in the oxidative hydroxylation step of this invention are prepared by the reaction of some tertiary amines with two molar equivalents of hydrogen peroxide or by the reaction of a tertiary amine oxide withone molar equivalent of hydrogen peroxide. Amine oxide peroxides are anovel class of oxidizing agents. For the most part, they have a higher oxidation potential than the hydrogen peroxide from which they were prepared.

The amine oxide peroxides of the present invention are oxide peroxides, e.g., 'dimethylethanolamine oxide per oxide, pyrrolidylethanol oxide peroxide, piperidyletlianol oxide peroxide, etc. Of these amine oxide peroxides, triethylamine oxide peroxide and N-methylmorpholine oxide peroxide are especially advantageous.

The organic polyvalent iodo oxides which may be employed in the oxidative hydroxylation step of this invention are organic iodo compounds having at least one titratable oxygen atom attached" to the iodine atoms. The presence of a titratable 'iodooxide oxygen atom can be determined in the usual manner with KI, acid and sodium-thiosulfate. The known examples of these iodo oxides are iodoso, iodyl an'diodoxy compounds and' salts thereof. The iodonium compounds-are not included in the term iodo oxides as used herein since the hydroxy group of the iodonium compounds is ionic in nature and is not therefore directly attached to the iodine atom, but merely associated with .it ionically. The iodoso compounds have one oxygen atom attached to the iodine atom; the iodoxy compounds have. two oxygen atoms attached.

Anexcellent reference to these iodo oxides is' Willgerodt, Die OrganischemVerbindungen Mit Mehrwertigcm Iodj F. Enke, Stuttgart (1914). Many iodo oxides are disclosed in this reference.

Iodine, Chem. Rev., 32, 249 (1943); Sidgwick, Chemical Elements and Their Compounds, vol. II, 1243-1260, Oxford Univ. Press (.1950); and Mason et al., J. Chem. Soc., 1935, 1669. The latter reference discloses the iodyl compounds.

From these references, it appears that iodo oxides can be prepared from aryl iodo compoundsor other vinyl iodides whose double bond is also modified in some way, e.g., by halogenation, as in a-chloro-iodoethylene, chloroiodofumaric acid or ot-chloro-iodoacrylic acid.

Examples of the known aryl iodo oxides include iodosobenzene, phenyliodosoacetate, diphenyliodyl hydroxide Other references include. R. Sandin, Organic Compounds of. Polyvalent' and acetate, phenyliodosopropionate, iod'oxybenzene, the

etc... The-heterocyclic aryl iodo'oxides, e.g., of the'pyri dine, thiophene andfuran series, do not appear to be known, but are included in the term aryliodo oxide."

The preferred organic polyvalent iodo oxides employed in the processof the present invention are the carbocyclic' Of these the aryliodoso compounds aryl iodo oxides. are preferred, e.g., iodosobenzene and phenyliodosoacetate, which have been found to give especially good results- The iodoxy compounds, for the mostpart, are very insoluble in organic solvents, and therefore do not usually give as satisfactory results as the corresponding iodoso compounds with respect to reaction rate and/or yield of 17-hydroxy-20-keto product.

The preferred aryl. iodoso compounds are ordinarily" prepared by the reaction of any aryl iododichloride with a base, e.g., sodium hydroxide. salts can be prepared by the reaction of an aryl iodide with the selected organicv peracid. The. iodoxy compounds are preparedby boiling the corresponding iodoso compounds in water or by oxidizingan aryliodide with,

for. example, Carosacid. The iodyl hydroxides are preparedby the reaction of anaryl iodoxy compound with two molar equivalents of sodium hydroxide in a one normal aqueous solution of sodium hydroxide at zero degrees centigrade for about 1.5 hours. See .Mason (loc. cit.). The salts of aryl iodyl hydroxy compounds.

are prepared by precipitating the aryl iodyl hydroxide as the carbonate and reacting the carbonate with the selected acid.

In carrying out the oxidative hydroxylation step of the invention, the. starting steroid is advantageously dissolved in. an inert organic solvent, for example, tertiary butylalcohol, diethyl ether, tetrahydrofuran, orthe like,

and the hydroxylating agent preferably osmium. tetroxide,

and the oxidizing agent mixed therein. Advantageously,

thoughnot necessarily, the hydroxylating agent is added.- Advanta geously also, the osmium tetroxide and the oxidizing.

after. the addition of the oxidizingv agent.

The amount of oxidizing agent theoretically required. to produce a 17-hydroxy-20-keto-2l-acyloxy steroid is two oxidizing equivalents for each mole of osmate ester formed in the reaction. that in the process of this invention, more than the theoretical amount of oxidizing agent is ordinarily necessary to obtain a complete reaction. For optimum results in the process of this invention, therefore, it is usually necessary to use theoxidizing agent-in excess of the theoretical amount.

about 2.75 equivalents of amine oxide peroxide or aryl iodo oxide, calculated on the starting steroid. The course are ordinarily obtained using between about 2.2 and determined by the titration of aliquot portions for residual oxidizing agent. Ordinarily, the presence of small amounts of water in the reaction mixture does not adversely affect the yield of desired product. However, to ensure optimum yields of desired product when employing hydrogen peroxide or an amine oxide peroxide, the reaction advantageously may be performed under substantially anhydrous conditions, e.g., in dry tertiary butyl alcohol, or like solvent.

The reaction temperature for the oxidative hydroxylation step normally is between about fifteen and about thirty degrees centigrade although higher or lower temperatures are operable, e.g., between ab'outminus ten and about plus seventy degrees centigrade. In place of thesolvents noted above, there maybe usedany inert solvent. which is. a, solvent forthe. reagents: Suitable The aryl iodoso acid.

It has been found, however,

For example, optimum results or ordinarily obtained using between about 2.2 and tetrahydrofuran, tertiary butyl alcohol, tertiary amyl alcohol, ethanol and methanol.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 Z-glyoxalation. of I I [3-hydroxy-2I-acetoxy-4J 7(20) pregnadiene-S-one A solution of 18.62 grams (0.05 mole) of llfi-hydroxy- 21-' acetoxy-4,17(20)-pregnadiene-3-one was prepared in 300 milliliters of dry tertiary butyl alcohol by heating the mixture at seventy degrees centigrade. The solution was cooled to 55 degrees centigrade and to the stirred solution, protected from atmospheric oxgen by bubbling nitrogen therethrough, was added 11.5 grams (0.10 mole) of methyl oxalate followed by a solution of 4.05 grams (0.075 mole) of sodium methoxide dissolved in sixteen milliliters of methanol. A thick, pale yellow precipitate soon appeared. Stirring was continued for ten minutes and the mixture was then diluted with 300 milliliters of anhydrous ether. Stirring was continued for an additional fifteen minutes and the mixture then filtered. The pale yellow-green precipitate was washed and dried at room temperature in a vacuum. The yield of about 24 grams of precipitate consisted primarily of a sodium enolate of 2-methoxy-oxalyl-1lfl-hydroxy-Zl-acetoxy- 4, l 7 20 -pregnadiene-3 -one.

The precipitate was dissolved in 250 milliliters of water and the solution acidified with dilute hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried. There was thus obtained 18.71 grams of an amor hous powder consisting essentially of 2-methoxyoxalyl-1lB-hydroxy-2l-acetoxy-4,17- (20)-pregnadiene-3-one which melted at eighty to 95 degrees centigrade and which gave a positive red-brown ferric chloride test.

EXAMPLE 2 Z-glyoxalation of 1 1 3-h ydroxy-ZI -acetxy-4,1 7 (20) pregnadiene-3 one Following the procedure described in Example 1, 2-ethoxy-oxa1yl-1 lfi-hydroxy-Z 1-acetoxy-4, 17 20) -pregnadiene-B-one and its sodium enolate is produced by the re action of 1lfl-hydroxy-Z1-acetoxy-4,17(20)-pregnadiene- 3-one with diethyl oxalate and sodium ethoxide.

Following the procedure described in Example 1, other 21-esters of 2-methoxyoxalyl-1 15,21-dihydroxy-4, 17 20) pregnadiene-3-one are prepared by substituting the corresponding 2l-ester of 11,3,2l-dihydroxy-4,17(20)-pregnadiene-B-one as the starting steroid of the reaction described in Example 1. Examples of Z-methoxyoxalyl- 1lfl-hydroxy-Zl-acyloxy-4,l7(20)-pregnadiene-3-ones thus prepared include those wherein the acyl group is the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, preferably a lower-aliphatic acid containing from one to eight carbon atoms, inclusive, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, hexanoic, diethylacetic, triethylacetic, octanoic, or other aryl, alkaryl, aralkyl or cycloalkyl, acids, e.g., benzoic, naphthoic, phenylacetic, 2,4,6-triethylbenzoic, cyclopentylformic.

Similarly, .other 2-alkoxyoxalyl-1lfl-hydroxy-Zl-acyloxy-4,17(20)-pregnadiene-3ones are prepared by the reaction .of 11;3,21-dihydroxy-4,17(20)-pregnadiene-3-one or selected 21-ester thereof with a di-lower-alkyl ester of oxalic acid, e.g., dipropyl oxalate, methyl propyl oxalate, methyl butyl oxalate, methyl amyl oxalate, methyl hexyl oxalate-methyl heptyloxalate, methyl octyl oxalate, etc.

EXAMPLE 3 I I fl-hydroxy-ZI -acetoxy-4 ,1 7 20 pregnadiene-3-one A mixture of 150 milliliters of dry benzene and a solution of 8.10 grams (0.015 mole) of sodium methoxide in 33 milliliters of methanol was distilled in a nitrogen atmosphere until sixty milliliters of distillate was collected. The remaining suspension of sodium methoxide in benzene was cooled to fifty degrees centigrade and 18.5 grams (0.25 mole) of ethyl formate was then added. After stirring the mixture for fifteen minutes, a solution of 3-keto-1 1B-hydroxy-2l-acetoxy-4, 17 (20 -pregnadiene- 3-one in 300 milliliters of dry benzene at fifty degrees centigrade was rapidly added thereto. The temperature of the mixture was gradually reduced to about 25 degrees centigrade while stirring was continued for one hour. There was then added 250 milliliters of anhydrous ether followed by further stirring for an additional hour Z-formylation of whereafter another 250 milliliter portion of ether wasv standing. To the stirred mixture was then added 500.

milliliters of water and the stirring continued until all of the solid had dissolved. The aqueous layer was separated, washed with ether and then acidified with dilute hydrochloric acid. Theresulting precipitate was collected by filtration, washed with water and dried. There was thus-obtained 12.14 grams of a mixture consisting essentially of 2 formyl 115 hydroxy-21-acetoxy-4,17(20)- pregnadiene-3-one which melted at to 123 degrees centigrade and which gave a positive deep violet ferric chloride test.

Following the procedure described in Example 3, other 21-esters of 2-formyl-1 15,2 1 -dihydroxy-4, 17 (20 -pregnadiene-B-one are prepared by substituting the corresponding 2l-ester of 11,8,21-dihydroxy-4,17(20)-pregnadiene-3- one as the starting steroid'of the reaction described in Example 3. Examples of 2-formyl-11{3-hydroxy-21-acyloxy-4,17(20)-pregnadiene-3-ones thus prepared include those wherein the acyl group is the acyl radical of a loweraliphatic acid, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, hexanoic, diethylacetic, triethylacetic, octanoic, etc.

EXAMPLE 4 Z-carboxylation of 1 IB-hydroxy-Zl -acet0xy-4,I 7(20) pregnadiene-3-one Following the procedure described in Example 1, 2- carbomethoxy-l1,8-hydroxy-21-acetoxy-4,17(20) pregnadiene-3-one and its sodium enolate is'produced by the reaction of 1118 hydroxy-2l-acetoxy-4,l7(20)-pregna- 1 droxy-4,l7(20)-pregnadiene-3-ones and their alkali-metal enolates are prepared by the reaction of 115,21-dihyaccomm- 13 droxy-f4,17(20.)-pregnadiene-3:one with the selectedlowerealkyl diester of oxalic acid and alkali-metal condensation catalyst, wherein at least one of the alkyl groups of the dialkyl ester of oxalic acid corresponds to the alkyl group of the thus-produced alkoxyoxalyl group. 2- formyl 115,21 dihydroxy 4,l7(20)-pregnadiene-3-one alnd 2-carbo-lower-alkoxy -'115,21'- dihydroxy 4,17(20)- pregnadiene-B-one are prepared by substituting, respectively, a lower-alkyl ester of formic acid and a lower-alkylester of carbonic acid for the dimethyl oxalate in the reaction described above.

,Other alkali-metal enolates are prepared by thereaction of a solution of, the free enol of a 2-lower-alkoxyoxalyl 115,2l-dihydroxy-4,17(20)-pregnadiene-3-one or 21-ester thereof with a solution of an alkaline alkalimetal compound, e.g., potassium hydroxide, potassium tertiary butoxide, lithium hydroxide, lithium 'methoxide, etc., or by substituting potassium tertiary butoxide, lithium methoxide'or other alkali-metal base condensation catalyst in the reactions described in Examples 1 to- 5.

, EXAMPLE 6. Z-methy'l-Z-methoxyoxalyl-I I5-hydroxy-21 -actxy-. 4,1 7 (20) -pregnadiene-3-one A mixtureof. 4.70 grams of crude Z-methoxyoxalyl- 11 -hydroxy-2l-acetoxy-4, 1 7( -pregnadiene-3-one, obtained according to the method of Example l,'ten grams of anhydrous potassium carbonate, fifteen milliliters of methyl iodide and 100 milliliters of acetone were stirred at about degrees centigrade for forty hours. Water was then added and the mixture extracted thoroughly with rnethylene chloride. The extract was washed with water, dried and the solvent distilled to leave a glassy residue consisting essentially of 2-meth'yl-2methoxyoxalyl-l'15-hydroxy-2l -acetoxy-4, l7 20) -p regnadiene-3f-one.

Similarly, other 2-lower-all yl-2-alkoxyoxalyl-1l'5-hydroxy 21 acyloxy-4,17(20) p'regnadiene-il-ones are'prepared by reacting a 2-alkoxyoxalyl-l15-hydroxy-21-aeyloxy-4,17(20) -pregnadiene-3-one with an alkyl halide, e.g., methyl: bromide, ethylbromide, propyl bromide, but'yl bromide, amyl bromide, hexyl bromide, heptyl bromide, octyl bromide. etc.,.to produce the corresponding 2-alkylated product wherein the alkoxy and acyloxy groups correspond to those of the starting2-alkoxyoxalyl- 1.15-hydroxy-21-acyloxy-4,l7(20) pregnadiene-3-one and the. alkyl group corresponds to that of the alkyl halide,

e,g., 2-methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, etc., 2-methoxy,.ethoxy, propoxy, butoxy, amy oxy,

hexyloxy,hep tyloxy, octyloxy, etc., and ZI-formyloxy, I

acetoxy, propionyloxy,,butyryloxy,,valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, etcv If the starting 2-alkoxyoxalyl steroid to be alkylated is, 2.1-.esterified, thereaction product may, depending upon the easeofhydrolysisor alcoholysis of the 2l+ester group and the alkylation conditions, produce a reaction product consisting, at least in part, of 2,-alkylated, steroid, having a 21-hydroxy. group. Examples of 21-ester groups quite resistant to hydrolysis. or alcoholysis are '21-trimethylacetate and 21 triethylacetate. Other 21-,esters may, if the alkylation reaction contains methyl or ethyl alcohol, be partially or completely. convertedto a 21-hydroxy group. v -EXAMPLB 7 Z-methyl-Z-formyl-I I5,21-dihydr0xy-4,17('20) I pregnadiene-3-one Following the procedure described in Example 6, but substituting the crude 2-formyl-115-hydroxy-21-acetoxy- 4,17(20)-pregnadiene-3-one, obtained according to the method described in Example 3, as starting steroid, there is thus-produced 2-methyl-2-formyl 1'15-hydroxy-2l-acet-.

:employedin the reaction described Example 7-, there is thus-produced thej corresponding ZQIoWeI-alkyLZ- formyl' 115,21- dihydroxy'- 4,17(20)"- pregnadiene;--3-" ones'wherein the, lower-alkyl group is, for example, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, etc. Similarly,

starting with a 2-formyl-115'hydroxy-21--acyloxy-4,17: (20)-pregnadiene-3-one wherein the acyloxygroup is, for. example, acetoxy, propionyloxy, butyryloxy, valeryloxy;

Following the procedure described in Example 6,, but) substituting 2-carbomethoxy-1.15-hydroxy-21-acetoxy-4, 17(;20)=pregnadiene-3-one,as, the starting steroid, there: is thus-produced 2-rnethyl-2-carbomethoxy-1lfl-hydroxy- 21-acetoxy-4,17. 20)-pregnadiene-3-one. Substituting other lower-alkyl halides as the alkylati'ng agent in the above reaction is productive of other 2-loweralkyl- 21 carbomethoxy 115 hydroxy- 21, -,acetoxy- 4,17(20)-pregnadiene-3-ones wherein theQlower-alk'yl group corresponds to that of the alkylating agent.

Substituting other 2 carbo-lower-alkoxy-1l5-hydroxy- 21-acetoxy-4,l7(20)-pregnadiene-3-ones as the starting steroid, in the reaction described above is, productive of the corresponding 2,-methylP2-carbo-lower alkoxy-115- hydroxy-21-acetoxy-4,17(20 )-pregnadiene-3-ones..

Substituting 2- (trifiuoroacetyl)-1 15-hydroxy-21-acetoxy- 4,17(20)-pregnadiene-3eone as starting steroid in the re,- action described in Example 6 is productive of 2 -methyl- 2 (trifiuoroacetyl) 115.- hydroxy 21, acetoxy 4,,17 (20)-pregnadiene-3-one.

EXAMPLE 9 The glassy residue of crude 2-methyl-2-methoxyoxalyL 115-hydroxy-2l-acetoxy-4,17(20)-pregnadiene-3-one, obtained according to the method described in Example 6, was dissolved in fifty milliliters of methanol'- to which was then added three milliliters of a 25 percent solution of sodium methoxidein'methanol. The now red [solution was stirred for two hours at about 25 degrees centi= grade. The mixture was then diluted with about 200 milliliters of water and extracted thoroughly with methylene chloride. The combined methylene chloride extracts were washed with water, dried and the solvent then distilled therefrom, leaving a steroidal. residue consisting essentially of 2-methyl-115,21-dihydroxy-4,17(-20)-pregnadiene-B-one. The thus-producedZ-methyl-l15,21-dihydroxy-4,17'( 20)-pregnadiene-3-one is purified by chromatography over Florisil synthetic magnesium silicate developed with Skellysolve B hexane hydrocarbons containing increasing amounts ofacetone.

Similarly, 2 methyl? 115,21 dihydroxy 4,17 (20)- pregnadiene-B-one isp-repared bysubstituting, asstarting steroid vfor the, reaction described above, another Z-methyl- 2 .lower,-- alkoxyoxalyl 115 hydroxy -2'1 acetoxy 4,17(20)-pregnadiene-3-one, e.g., wherein the loweralkoxyv'groupiis ethoxy, propoxy, butoxy, amyloxy, hexyl- 'oxy, heptyloxy, octyloxy, etc., for the 2-methyl-2-methoxyoxalyl hydroxy 21 acetoxy 4,17(20) pregnadiene-3-oneemployed in Example 9'.

Following the procedure described in Example 9, other 2 lower alkyl 115,21 dihydroxy 4',17(20) pregnadiene-Z-ones areprepared wherein the lower-alkyl group is;" -for example, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl; etc., by substituting a Z-l'ower-alkyl-Z-lower-allte oxyoxalyl- 115,21 dihydroxy 4,l7(20) pregnadiene EXAMPLE, 10

Z-methyl-I 15,21-dihydroxy-4J 7 -pregnadiene- 3-o ne Following the procedure described in Examples 6 and 9, 2 formyl 116,21 dihydroxy 4,17(20) pregnadiene-3-one was converted in 35 percent yield to Z-methyll1B,2l-dihydroxy-4,17(20)-pregnadiene-3-one.

In the same manner, 2-methyl-llB,2l-dihydroxy-4,17 (20)-pregnadiene-3-one is prepared by substituting the sodium enolate of 2-formyl-l15,21-dihydroxy-4,17(20)- pregnadiene-S-one, the sodium enolate of '2-ethoxyoxalyll15,21-dihydroxy-4,l7(20)-pregnadiene-3-one, or another alkali-metal enolate of either of these compounds, as the starting steroid in the reactions described in Examples 6 and 9.

Similarly, substituting a 2-lower-alkyl-2-formyl-115,21- dihydroxy-4,17(20)pregnadiene-3-one or 21-lower-acyloxy ester thereof wherein the alkyl group is, for example, methyl, propyl, butyl, amyl, hexyl, heptyl, octyl, etc., as the starting steroid in the reaction described in Example 9, there is produced a 2-lower-alkyl-1113,2-1-dihydroxy- 4,17 (20)-pregnadiene-3-one wherein the lower-alkyl group corresponds to that of the starting steroid.

Similarly, 2 methyl 115,21 dihydroxy 4,17(20)- pregnadiene-3-one isprepared, according to the method of Example 9, by substituting 2-methyl-2-carbomethoxy- 11s hydroxy 21 acetoxy 4,17(20) pregnadiene 3- one or other 2-methyl-2-carbo-lower-alkoxy-l lB-hydroxy- 2l-acyloxy-4,17(20)-pregnadiene-3-one, or 2-methyl-2- (trifiuoroacetyl) 11;] hydroxy 21 acyloxy 4,17(20)- pregnadiene-B-one wherein the acyl group is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, as starting steroid in Example 9.

EXAMPLE 1 1 Z-ethyl-I 1fi,21-dihydr0xy-4,1 7 (20 -pregnadiene-3-0ne Followingthe procedure described in Example 9, but substituting 2 ethyl -2 methoxyoxalyl 11p hydroxy- 21-acetoxy-4,17(20)-pregnadiene-3-one as the starting steroid, there'is thus-produced 2-ethyl-113,21-dihydroxy- 4,l7(20)-pregnadiene-3-one.

EXAMPLE 12 2 methyl 11p hydroxy 21 acetoxy 4,1? 20) pregnadiene-3-0ne The crude residue obtained from a reversal reaction performed exactly as described in Example'9 was dissolved in a mixture of ten milliliters of acetic anhydride and ten milliliters of dry pyridine. The mixture was maintained at about 25 degrees centigrade for about sixteen hours. The excess acetic anhydride was then decomposed with ice water and the resulting gummy precipitate was extracted with benzene. The benzene solution was washed with cold dilute hydrochloric acid, cold aqueous sodium bicarbonate and finally with water and then dried. The dried benzene solution was poured over a chromatographic column of 100 grams of Florisil synthetic magnesium silicate. The column was developed with 1350 milliliters of Skellysolve B hexane hydrocarbons containing five percent acetone followed by 750 milliliters of Skellysolve B plus 7.5 percent acetone and then 150 milliliters of acetone. The eluates were collected in 150 milliliter fractions. Eluate fractions 4 to 8 contained a total of 1.71 grams, a yield of 44 percent, calculated on the starting 2-methoxyoxalyl-11,3,2l-dihydroxy- 4,17(20)-pregnadiene-3-one, of crystalline 2-methyl-11phydroxy 2 1 acetoxy 4,17(20) pregnadiene 3 one. Recrystallization of this product gave v2-methyl-111S-hydroxy 21 acetoxy 4,l7(20) pregnadiene 3 one melting at 182 to,l84.5 degrees centigrade,,having an [M of plus degrees in chloroform, an ultraviolet absorption of 15,025 at 242 millimicrons and the analysis below;

Calculated for C l-1 0 C, 74.57; H, 8.87. Found: C, 74.32; H, 8.79.

Similarly, 2 methyl 11,8,21 dihydroxy 4,17(20) pregnadiene-3-one is converted to other Z-methyl-llfl-hydroxy 21 acyloxy 4,17(20) pregnadiene 3 ones by esterification of the 2l-hydroxy group, e.g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the-presence of an esterification catalyst, etc., 2 methyl 1113,21 dihydroxy 4,17(20) pregnadiene 3 4 one is similarly' converted to other 21-esters thereof. Examples of 2- methyl llfl hydroxy 21 acyloxy 4,17(20) pregnadiene-3-one prepared include 'thosewherein the acyl group is the acyl radical of, for example, alower-aliphatic acid, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 2-m ethylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, the optically active abietic, a-ethyliso-valeric, an acyclic acid, e.g., 35-hydroxycholanic, 3phydroxyetiocholanic, :yclopropylideneacetic, a cycloaliphatic acid, e.g., cyclopentylformic, cyclopentylacetic, p-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, i-cyclohexylpropionic, an aryl or alkaryl acid, e.g., benzoic, 2,3 or 4-methylbenzoic, 2,3-, 2,4--, 2,5-, 2,6-,I'3,4-, and 3,5-dimethylbenzoic, ethylbe nzoic, 2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic, a-naphthoic, 3-methyl-a-naphthoic, an aralkyl acid, e.g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid (which can be converted to water soluble, e.g., sodium, salts) e.g., succinic, glutaric, a-methylglutaric, fl-methylglutaric, Bfi-dimethylglutaric, adipic, pimelic, 'suberic, a hydroxyacid, e.g., glycolic, lactic, citric, tartaric, d-malic, d-glyceric, mannonic, gluconic, salicylic, an aminoacid, e.g., glycine, diglycollamic, triglycollamic, methylglycine, dimethylgly cine, diethylglycine, para-aminosalicylic, para-aminobenzoic, other hetero-substituted acids, e.g., ethylmercaptoacetic, benzylmercaptoacetic', cyanoacetic, chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic, thioglycolic, 2,3,4-trimethoxybenzoic, a-napthoxyacetic, p-pyrrolidylpropionic, carbamic acids, e.g., carbamic acid, phenylcarbamic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic, allophanic, or a heterocyclic acid, e.g., p-furylcarboxylic, N-methylpyrrolidyl-2-carboxylic, a-picolinic, indole-Z-czirboxylic, 6-hydroxyindolyl-3-acetic, N-methylmorpholyl-Z-carboxylic, lysergic, pyrrolyl-2-carboxylic, or other acyl acid. 1

Alternatively, the 2l-hydroxy group of the 2 methyl- 115,21 dihydroxy 4,17(20) -'pregnadiene 3 one can be converted to another 21-derivative, leaving the remainder of the molecule unchanged. Examples of such 2l-derivatives are ZI-ethers, e.g., 2l-methoxy, ethoxy, benzyloxy, propoxy, a-tetrahydropyranyloxy,' (,B-carbethoxy B cyano)ethylenoxy, 5,5 dicarbethoxy ethenyloxy, ,8 ketocyclohexenyloxy, fl trichloro a acetylethoxy, chloromethoxy, dimethylmethoxy, diethylmethoxy, dimethylethoxy, diethylethoxy, 21-thioesters, e.g., acetylrnercapto, B cyclopentylpropionylmercapto, triethylacetylmercapto, trimethylacetylmercapto, propionylmercapto, 21-thione esters, e.g., thioacetyloxy, thiopropionyloxy, thio B cyclopentylpropionyloxy, thiotriethylacetyloxy, thiotrimethylacetyloxy, imido .derivatives of acetyl esters, e.g., acetimido-oxy, 2l-esters of mineral acids, e.g., 21-phosphate, 21-sulfonate, 2l-sulfinate, 21- methylphosphate, 21,-m ethylsulfonate, .2l-methyl'sulfinate, 21-b1'0m05flu0ro and. 21-chloro, esters of the carbonic 17 acids, e.g., Zhcarbonate, 21-(triethoxy)methoxy, 21-sul fonyloxy, e.g., 2l-para-toluenesulfonyloxy, etc.

EXAMPLE 13 2 ethyl 115 hydroxy 21 acetoxy 4,17(20) pregnadiene-3-one Following the procedure described in Examples 6, 9 and 12, but substituting ethyl iodide for the methyl iodide as the alkylating agent, 1lfi-hydroxy-Z1-acetoxy-4,17(20) pregnadiene-3-one was converted to 2-ethyl-11fi-hydroxy- 2l-acetoxy-4,l7(20)-pregnadiene-3-one. The reaction product from the acetylation was dissolved in methylene chloride and poured over a column of Florisil synthetic magnesium silicate. The 2-ethyl-1lfl-hydroxy-2l-acetoxy- 4,l7(20)-pregnadiene-3-one was eluted from the column I with Skellysolve B hexane hydrocarbons plus five percent acetone and melted, after crystallization from a mixture of acetone and Skellysolve B, at 149 to 151 degrees centigrade, and had the analysis below.

Calculated for C H O C, 74.96; H, 9.06. Found: C, 75.23; H, 9.17.

Similarly, other 2-lower-alkyl-11B,21-dihydroxy-4,17 (20)-pregnadiene-3-ones are esterified to produce the 2- lower alkyl 11B hydroxy 21 acyloxy 4,17(20)- pregnadiene 3 ones wherein the lower-alkyl group is, for example, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, etc., and the acyl group is the acyl'radical of an acid named in Example 12 or the paragraph following.

EXAMPLE 14 Z-methyl-I 15,1 7u-dihydr0xy-21-acet0xy-4- pregnene-3,20-dione To a solutionof 1.40 grams (3.63 millirnoles) of 2- methyl 11/3 hydroxy 21 acetoxy 4,17(20)-pregnadiene-3-one in seventy milliliters of dry tertiary butyl alcohol was added at room temperature'nine milliliters of dry pyridine, 5.8 milliliters of dry tertiary-butyl alcohol solution containing 1.37grams (9.1 millimoles) of N- methylmorpholineoxide peroxide, and ten milligrams of osmium. tetroxide, in that order. The resulting solution was stirred at between 25 and thirty degrees centigrade for eighteen hours. There was then added 150 milliliters of water to the mixture which was then extracted thoroughly with methylene chloride, the methylene-chloride solution washedwith water, cold dilute hydrochloric acid, cold aqueous sodium bicarbonate, water and then dried. The solvent was distilled from the dried solution at reduced pressure. The crude residue was dissolved in methylene chloride and poured over a column of 110 grams of Flon'sil synthetic magnesium silicate. The column was developed with 175 milliliter portions of solvent of the following composition and order: eight of Skelly solve' B plus ten percent acetone, seven of Skellysolve B plus twelve percent acetone, two of Skellysolve B plus fifteen percent acetone, and one of acetone. The Skellysolve B plus five percent acetone eluted 331 milligrams of starting steroid. The Skellysolve B plus twelve. percent acetone eluted 784 milligrams, a yield of 69 percent calculated on the starting steroid which reacted, of Z-methyl- 115,17 dihydroxy 21 acetoxy 4 pregnene 3,20- dione which, aftercrystallization from ether, melted at 133 to-135 degrees centigrade, had anlrxJ of plus- 158 degrees in chloroform andthe analysis is below.

Calculated for C H O C, 68.87; H, 8.19. 'Found; C, 68.38; H, 8.52. Subsequent preparations of 2 methyl 11,8,17oc-dihydroxy 21 ---acetoxy 4 pregnene. 3,20 dione gave crystals melting at 171 to 171.5 when crystallized from a mixture of. ethyl acetate and Skellysolve B, having an [al of plus 164 degrees, an E of 15,125, the'same papergrarn and infrared spectrum analysis as the'product of; the previous preparation, and a carbon-hydrogen analysis almost identical to the calculated.

. Similarly, other. 2 methyl 115 hydroxy -2;1- aey xy ,1 9 Pr na ie 3 n aresirnilarly converted to the corresponding 2 methyl 11fi,17u1 dihydroxy 21 acyloxye 4 pregnene 3,20 diones wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e.g.,:formic, .propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 2 methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, the optically active abietic, a-ethylisovaleric, an acyclic acid, e.g.,'3B-hydroxycholanic, 3fi-hydroxyetiocholanic, cyclopropylideneacetic, a cycloali'phatic acid, e.g., cyclopentylformic, cyclopentylacetic, fl-cyclopentylpropionic, cyclohexylformic, cyclohexylace' tic', B-cyclohexylpropionic, an aryl or alkaryl acid, e.g., benzoic, 2,3, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5 dimethylbenzoic, ethylbenzoic, 2,4,6 trimethylbenzoic, 2,4,6-triethylbenzoic, wnaphthoic, 3-methyl-anaphthoic, an aralkyl acid, e.g., phenylacetic, phenylprop-ionic, diphenylacetic, triphenylacetic, a dibasic acid (which can be converted to water soluble, e.g., sodium, salts) e.g., succinic, glutaric, u-methylglutaric, B-methylglutaric, [LB-dimethylglutaric, adipic, pimerlic, suberic, a hydroxyacid, e.g., glycolic, lactic, citric, tartaric, dmaleic, d-glyceric, mannonic, gluconic, salicylic, an aminoacid, e.g., glycine, diglycollamic, triglycollamic, methylglycine, dimethylglycine, diethylglycine, para-aminosalicylic, para-aminobenzoic, other hetero-substituted acids, e.g., ethylmercaptoacetic, benzylmercapt'oacetic, cyanoacetic, chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic, thioglycolic, 2,3',4-trimethoxybenzoic, anapthoxyacetic, fi-pyrro-lidylpropionic, carbamic. acids, e.g., carbamic acid, phenylcarbamic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic, allo-phanic,or a heterocyclic acid, e.g., fi-furylcarboxylic, N-methylpyrrOlidyl-Z- carboxylic, e-picolinic, indole-Z-carboxylic, 6 hydroxyindolyl 3 acetic, N methylmorpholyl 2 carboxylic, lysergic, pyrrolyl-Z-carboxylic, or other acyl acid.

Alternatively, the starting steroid may be a Z-methylhydroxy 21 substituted 4,17(20) pregnadiene- 3 one wherein the 21-substituent is a 21-ether, e.g., 21- methoxy, ethoxy, benzlyoxy, propoxy, a tetrahy'- dropyranyloxy, dicarbethoxyethenyloxy, B ketocyclohexenyloxy, fi trichloro-a-acetylethoxy, chloromethoxy, dimethylmethoxy, diethylmethoxy, d'imethylethoxy, diethylethoxy, 21-thioesters, e.g., acetylmerc-apto, ,8-cyclopentylpropionylmercapto, triethylacetylmercapto, trimethylacetylmercapto, propionylmercapto, 21-thione esters, e.g., thioacetyloxy, thiopropionyloxy, thio-p-cyclopentylpropionyloxy, thi'ot'riethylacetyloxy, thiotrimethylacctyloxy, imido derivatives of acetyl esters, e.g., acetimido-oxy, 21-esters of mineral acids, e.g., 21-phosphate, 2l-sulfonate, 21-sulfinate, 21- methylphosphate, 2l-methylsulfonate, 21-methyl'sulfinate, 21-bromo, fluo-ro or 2l-chloro, esters of the sulfonyloxy, e.g., 21-para-toluenesulfonyloxy, etc., to produce a 2 methyl-11,8,17ot-dihydroxy-21-substituted-4-pregnene-3,20- dionewherein the 21-substituent is that of the starting steroid.

EXAMPLE 15 Z-ethyI-J 1B,] 7a-dihya'roxy-21 -acetoxy-4- pregnene-3,20-dione' Following the procedure described in Example 14, but substituting 2 ethyl 11,8 hydroxy 21 acetoxy 4,17 (20) pregnadiene 3 one as the starting steroid, there is thus produced 2 ethyl 11,13,17a dihydroxy 21- acetoxy 4 pregnene 3,20 dione. The crude reaction product from the oxidative hydroxylation was dissolved in methylene chloride which was poured over a column of Florisil synthetic magnesium silicate. The column was developed. inv exactly the manner described in Example 14 and the 2 ethyl 115,17m dihydroxy 21 acetoxy 4 pregnene 3,20 dione, was eluted with Skellysolve' B plus ten percent acetone and melted, after crystallization from dilute methanol, at 166 to 169 degrees centrigrade.

' Similarly, other 2 lower alkyl -1 15 hydroxy 21- acyloxy; 4,17 (20) pregnadiene- 3.- ones. are oxidae (fi-carbethoxy-[B-cyano)ethylenoxy, 3,;3-

etc.

EXAMPLE 16 2-methyl-1 1 [3,1 70tdihya'r0xy-21-acet0xy-4-pregnene- 3 ,2 O-dione To a solution of, 1.116 grams (3.0 millimoles) of Z-methyl-l l 3-hydroxy-2 l-acetoxy-4, l 7 (20) -pregnadivene3-onedissolved in sixty milliliters of tertiary butyl alcohol and 1.5 milliliters of pyridine is added, at 25 degrees centigrade, five milliliters of tertiary butyl alcohol containing 11.1 milligrams (0.044 millimole) of osmium tetroxide and 0.2 milliliter (0.11 millimole) of water. To the solution is then added 2.4 grams (7.5 millimoles) .of :phenyliodosoacetate, which completely dissolves within twenty minutes. When the reaction is substantially complete, twenty milliliters of water is added to the reaction mixture and then distilled at reduced pressure .to a volume of about twenty milliliters. An additional .twenty milliliters of water is added to the residue and the mixture thoroughly extracted with ethylene dichloride. The steroidal portion of the extract consists mainly of 2 -methyl 11,8,170; dihydroxy 21 acetoxy-4-pregnene- 3,20-dione. EXAMPLE 17 Z-methyl-I 1 [3,1 7a-dihydr0xy-2I -acetoxy-4-pregnene- 3,20-dine To a solution of 744 milligrams (2.0 millimoles) of Z-methyl-l lfl-hydroxy-Z1-acetoxy-4,17(20)-pregnadiene-3-one in thirty milliliters of tertiary butyl alcohol is added one milliliter of pyridine and 25 milligrams (0.1 millimole) of osmium tetroxide in eight milliliters of tertiary butyl alcohol. To the resulting solution is added 8.36 milliliters (5.0 millimoles) of an 0.6 molar solution of hydrogen peroxide in sodium dried tertiary butyl alcohol over a period of one hour and the mixture stirred for another hour.

The reaction mixture thus obtained is worked up as follows: 600 milligrams of sodium sulfite dissolved in .25 milliliters of water is added and, after stirring for five minutes, the resulting mixture is concentrated to about fifteen milliliters by distillation at a pressure of about fifty milliliters mercury absolute and the resulting concentrate then extracted with methylene chloride. The methylene chloride extract is dried. The steroidal product consists mainly of 2-methyl-11,8,170t-dihydroxy- 21-acetoxy-4-pregnene-3,20-dione. The glycol by-product is 2-methyl-1 1,8, 170:,2O-i1ihYdlOXY-2 1-acetoxy-4-pregnene- 3-one. The A steroids otherwise corresponding to the compounds of Examples 14 to 17, especially 2-methyl- 11,8,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione and 2- methyl 11,9,170t dihydroxy-21-acetoxy-1,4-pregnadiene- 3,20-dione, possess marked adrenal cortical hormone activity useful in the treatment of Addisons disease, rheumatoid arthritis, and inflammatory conditions of the skin, inner ear, nose and eye, of a wide variety. The preparation of a 2-lower-alkyl-11,6,170t-dihydroxy-21- acyloxy-l,4-pregnadiene-3,20-dione and the corresponding free 21-hydroxy compound, is given below, as exemplified for the preparation of the 2-methyl compound.

Dehydrogenation of Z-methyl-l15,21-dehydroxy-4,17 (20)-pregnadiene-3-one with a fusarium [Experientia, 9, 371-372 (1953)] is productive of 2-methyl-11,8,21- dihydroxy-1,4,17 (20)-pregnatriene-3-one. Substitution of this compound in the reaction described in Example 12, followedby the reaction of Example 14, is productive of Z-methyl-l15,1700-dihydroxy-2l-acetoxy-l,4-pregnadiene-3-one, which can be hydrolyzed to the free 21-hydroxy compound according to methods known in the art, and then reesterified to another 21-ester thereof, e.g., a A

the following sequence of reactions:

compound otherwise corresponding to the compounds named in the paragraph following Example 14.

Alternatively, 2-methyl-1 1B,1700,2l-trihydroxy-1,4-pregnadiene-3-one and 2l-esters thereof are prepared by hydrogenating 2 methyl 115,170: 4 dihydroxy 21 acetoxy-4-pregnene- 3,20-dione to produce 2-methy1-11fi,l70t-dihydroxy-21- acetoxya1lopregnane-3,20-dione; dibrominating this compound in glacial acetic acid containing some pyridine .to produce 2-methyl-2,4-dibromo-11p,170-dihydroxy-21- acetoxy-pregnane-3,ZO-dione and then dehydrobrominating this compound with pyridine, collidine, or semicarbazide followed by the decomposition of the semicarbazone according to methods known in the art, to produce 2 methyl 11531704 dihydroxy 21 acetoxy-1,4-pregnadiene-3,20-dione which can be hydrolyzed according to methods known in the art to produce 2-methyl-l1/3,17a,21- trihydroxy-1,4-pregnadiene-3,20-dione which, in turn, can be reesterified in the manner described hereinbefore to produce a A compound otherwise corresponding to the compounds described in the paragraph following Example 14.

I Treatment of a 2-lo/wer-alkyl-11B,170-dihydroxy-21- acetoxy-l,4-pregnadiene-3,20-dione, preferably 2-methyl, with a dehydrating agent, e.g., para-toluenesulfonic acid, P001 in pyridine, HCl in acetic acid, acetic or formic acid in the presence of SP is productive of the corresponding 2-lower-alkyl-170t-hydroxy-21-acetoxy-1,4,9(11)- pregnatriene-3,20-dione which, when reacted with N-bromoacetamide in the presence of aqueous perchloric acid, is converted to the corresponding 2-lower-alkyl-9u-bromo 11B,17a-dihydroxy-2l-acetoxy-1,4-pregnadiene-3 ,ZO-dione. Reaction of this compound with sodium methoxide and methanol converts the t-bromo-1l/3-hydroxy function to a 9: ll-fi-oxido group. Treatment of the thus-produced 2 lower alkyl 9: ll B oXido-c-hydroXy-21-acetoxy- 1,4-pregnadiene-3,20-dione with anhydrous hydrogen fluoride in methylene chloride at minus fifteen degrees centigrade is productive of 2-lower-alkyl-90t-fluoro-115, 17a dihydroxy 21 acetoxy-l,4-pregnadiene-3,20-dione, preferably the 2-methyl compound. Hydrolysis of this compound with aqueous sodium bicarbonate in methanol under nitrogen at room temperature is productive of the 2 lower alkyl 900 fluoro 1l5,17a,21-trihydroxy-l,4- pregnadiene-3,20-dione which can be reesterified according to one of the methods described in the paragraph following Example 14 to produce a A -9a-fiuo-ro compound otherwise corresponding to the esters described in the paragraph following Example 14. The corresponding 9a-Chl0r0 compounds are produced by substituting hydrogen chloride for the hydrogen fluoride employed in the reaction described above. These 900-fluoro and 9a-chloro compounds possess a high order of mineralocorticoid, glucocorticoid, and anti-inflammatory activity.

The 19-normethyl analogoues of the novel synthetic 2-lower-alkyl steroids of the present invention possessing thecortical hormone side chain, also possess pronounced anti-inflammatory and other adrenal cortical hormone activity. These compounds, i.e., 2-lower-alkyl-11 3,170,21- trihydroxy-19-normethyl-4-pregnene-3,ZO-dione, 2-loweralkyl 9a fluoro-11 3,17a,21-trihydroxy 19 normethyl- 4-pregnene-3,20-dione, 2-lower-alkyl-90z-chloro-11,8,17a, 21 trihydroxy-19-normethyl-4-pregnene-3,20-dione, and 2l-esters thereof, e.g., lower-aliphaticand preferably acetate, wherein the 2-lower-alkyl group is preferably methyl, are prepared instead of the corresponding 19-methyl compounds, by substituting the corresponding 2-lower-alkyl- 19-normethyl-1113,21-dihydroxy-4-pregnene, 3,20-dione for the 2-lower-alkyl-1118,21-dihydroxy-4-pregnene-3,20-dione as starting steroid in the production of a 2-lower-alkyl- 115,170: dihydroxy 21 acyloxy-4-pregnene-3,20-dione. The thus-produced 2-lower-alkyl-11,3,17a-dihydroxy-19- normethyl-Zl-acyloxy-4-pregnene-3,20-dione can then be converted to the other 19-normethyl compounds described 21 above in-thesame manner that the correspondingwmethylcompounds are prepared.

The starting 2 lower alkyl 1113,21 dihydroxy-l9,,- normethyl-3-one is prepared by converting 19-normethylprogesterone to 115,21-dihydroxy-19-normethyl-4,17(20)- pregnadiene-3-one according to the method described in US. Patent 2,790,814.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. Z-carbonyl 2 lower-alkyl 11/3 hydroxy-Zl-oxy- 4,1.7(20)-pregnadiene-3-one represented by the following fo mu a:

' (IJHr-Or-R CH ll HO- if on lower-alkyl wherein R is selected from the group consisting of hy'- drogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and wherein R is selected from the group consisting ofhydrogen, trifluoromethyl, lower-alkoxy and carbolower-alkoxy.

2. 2 lower alkoxyoxalyl 7 2 methyl 115,21 dihydroxy-4,17(20):pregnadiene-3-one represented by the following formula:

3 2 lower alkoxyoxalyl 2 methyl 11 S-hydroxy- 21-acyloxy-4,l7(20)-pregnadiene-3-one represented by the following formula:

wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive, and R is selected from the group consisting of hydrogen, triiluoro-methyl, lower-alkoxy, andrcarbo-loweralkoxy, with a lower-alkyl halide wherein the halogen has an atomic weight from 79 to 127, inclusive, to produce a 2 -.lower alkyl 2 carbonyl 11B hydroxy 2 1 oxy- 4,17(20)-pregnadiene!3-one.

8. The process of claim 7 wherein R ishydrogen, R is carbo-methoxy and the lower-alkyl halide is methyl iodide.

9. The process which comprises the steps of (1) alkylating the alkali-metal salt of a Z-carbonyl-llfi-hydroxy- 21-oxy-4,17(20)-pregnadiene-3-one represented by thefollowing formula:

wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelvecarbon atoms, inclusive, and R is selected from the group consisting of hydrogen, trifiuoromethyl, lower-alkoxy, and carbo-loweralkoxy, with a lower-alkyl halide wherein the halogen has an atomic weight from 35 to 127,, inclusive, to pro: duce a Z-carbonyl 2 lower-alkyll1/8 hydroxy 21-oxy 4,17(20)-pregnadiene-3-one and (2) removing the 2-car bonyl group of the latter thus-produced compound with an alkali-metal base and a compound selected from the group consisting of water and a lower-alkanol to produce a 2-lower-alkyl-1 l B-hydroXy-21-oxy-4, l7(20)-pregnadiene- 3-one.

10. The process of claim 9 wherein R is acetyl, R is ethoxy-oxalyl and the compound of step 2 isan alkanol containing less than three carbon atoms.

11. The process of claim 9 wherein R is hydrogen, R is methoxyoxalyl, the lower-alkyl halide is methyl iodide and in step 2 the alkali-metal base is an alkali-metal methoxide and the compound is methanol.

12. The process which comprises the steps of 1) alkylating the alkali-metal salt of a Z-carbonyl-llfi-hydroXy-21-oXy-4,17(20)-pregnadiene-3-one represented by the following formula:

wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and R is selected from the group consisting of hydrogen, trifluoromethyl, lower-alkoxy, and carbo-loweralkoxy, with a lower-alkyl halide wherein the halogen has an atomic weight from 79 to 127, inclusive, to produce a 2 carbonyl 2 lower alkyl 11/3 hydroxy 21 oxy 4,17() pregnadiene 3 one; (2) removing the 2-carbonyl group of the latter thus-produced compound with an alkali-metal base and a compound selected from the group consisting of water and a loweralkanol to produce a 2-lower-alkyl-1lfi-hydroxy-Zl-oxy- 4,17(20)-pregnadiene-3-one; and (3) esterifying the 2 lower alkyl 115,21 dihydroxy 4,17(20) prege nadiene 3 one with an acylating agent'to produce a 2 lower alkyl 11B hydroxy 21 acyloxy 4,17(20) pregnadiene 3 one.

13. The process of claim 12 wherein R'is acetyl, R is ethoxyoxalyl, the lower-alkyl halide is a methyl halide, the compound of step 2 is. an alkanolcontaining less than three carbon atoms, and the acylating agent of step 3 is an acetylating agent.

14. The process of claim 12 wherein R is acetyl, R is methoxyoxalyl, the lower-alkyl halide is methyl iodide, in step'2 the alkali-metal base is an alkali-metalmethoxide and the compound is methanol, and the acylating agent of step 3 is acetic anhydride.

15. The process of claim 12 wherein R is hydrogen, R is methoxyoxalyl, the lower-alkyl halide is methyl iodide, in step 2 the alkali-metal base is an alkali-metal methoxide, and the compound is methanol, and the acyl ating agent of step 3 is acetic anhydride.

16. A compound represented by the following formula:

wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inelusive.

17. 2 methyl 115,170; dihydroxy 21 acetoxy 4 pregnene 3,20 dione.

18. 2 ethyl 11 8,17 dihydroxy 21 acetoxy 4 pregnene 3,20 dione.

19. The process which comprises the steps of' (1)- wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and R is selected from the group consisting of hydrogen, trifluoromethyl, lower-alkoxy, and carbo-loweralkoxy, with a lower-alkyl halide wherein the halogen has an atomic weight from 79 to 127, inclusive, to produce 2 carbonyl 2 lower alkyl 1118 hydroxy 21 oxy 4,17(20) pregnadiene 3 one; (2) removing the Z-carbonyl group of the latter thus-produced compound with an alkali-metal base and a compound selected from the group consisting of water and a lower-alkanol to produce a 2-lower-alkyl-l1fi-hydroxy-21-oxy-4,17(20)-pregnadiene-3-one; (3) esterifying the 2-lower-a1kyl-1 15,21- dihydroxy-4,17(20)-pregnadiene-3 one with an acylating agent to produce a 2-lower-alkyl-11p-hydroxy-21-acyloxy- 4,l7(20)-pregnadiene-3-one; and (4) oxidative hydroxylating the 21-acyloxy compound with osmium tetroxide and an oxidizing agent to produce a 2lower-alkyl- 113,171- dihydroxy-Z1-acyloXy-4-pregnene-3,20-dione.

20. A compound represented by the formula:

CHQOH References Cited in the file of this patent UNITED STATES PATENTS 7 2,730,537 Nathan Jan. 10, 1956 2,774,776 Hogg et a1. Dec. 18, 1956 

1. 2-CARBONYL-2- LOWER-ALKYL -11B-HYDROXY-21-OXY4,17(20)-PREGNADIENE-3-ONE REPRESENTED BY THE FOLLOWING FORMULA: 